Human immunodeficienty virus (HIV) infection is suppressed but not eliminated by antiretroviral drugs. Viral persistence in the face of therapy has been explained by viral latency, lowered effectiveness of drugs in some anatomical sites and cell types, and cell-to-cell spread. These mechanisms allow for drug-sensitive virus to persist despite treatment. Understanding the persistence mechanism at work at different times after infection, including the time of initial infection immediately following transmission when reservoirs are first formed, will reveal if we are at the limit of what can be achieved with the current therapy paradigm of suppressing ongoing virus replication with drugs.

This short review discusses some of the possible reasons why HIV persists at different points on the infection timeline, focusing on the role ongoing replication may have in maintaining the infection despite drugs at early times postexposure.